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Iron is an essential element for the growth and proliferation of nearly all microorganisms. In the presence of oxygen, soluble ferrous iron is readily oxidized to its ferric form, which is predominantly insoluble at neutral pH. To overcome iron limitation, many bacteria synthesize and secrete low- molecular-weight, high-affinity ferric iron chelators, called siderophores, which are actively taken up as a complex with Fe3+ by a cognate ABC transport system. The main siderophores produced by streptomycetes are desferrioxamines. Here we show that several Streptomyces griseus strains, in addition, synthesize a hitherto unknown siderophore with a catechol-peptide structure, which we named griseobactin. The production is repressed by iron. We sequenced a 26-kb DNA region comprising a siderophore biosynthetic gene cluster encoding proteins similar to DhbABCEFG, which are involved in the biosynthesis of 2,3-dihydroxybenzoate (DHBA) and in the incorporation of DHBA into siderophores via a nonribosomal peptide synthetase. Adjacent to the biosynthesis genes are genes that encode proteins for the secretion, uptake, and degradation of siderophores. Knockout mutagenesis, complementation and heterologous expression confirmed the requirement of the dhb genes for synthesis and secretion of DHBA and of the entire biosynthesis gene cluster for biosynthesis and secretion of griseobactin. Griseobactin was purified and characterized; its structure is consistent with a cyclic and, to a lesser extent, linear form of the trimeric ester of 2,3-dihydroxybenzoyl-arginyl-threonine complexed with aluminum under iron-limiting conditions. This is the first report on the identification of the genes responsible for DHBA and catechol siderophore biosynthesis in Streptomyces.
